rs397517652
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_001267550.2(TTN):c.62780G>A(p.Arg20927His) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,612,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20927C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.62780G>A | p.Arg20927His | missense_variant | 304/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.3189-2194C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.62780G>A | p.Arg20927His | missense_variant | 304/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.417-8651C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 151978Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000809 AC: 2AN: 247138Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134114
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1460564Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 726536
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74350
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2017 | A variant of uncertain significance has been identified in the TTN gene. The R19286H variant (reported as R18359H due to the use of alternate nomenclature) has been reported as a variant of uncertain significance in one patient with DCM (Pugh et al., 2014); however, additional clinical and segregation information were not provided. The R19286H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this is a missense variant in a gene in which most reported pathogenic variants associated with cardiomyopathy are truncating/loss-of-function (Stenson et al., 2014). Nevertheless, the R19286H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Finally, this substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 27, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 04, 2012 | The Arg18359His variant (TTN) has not been previously reported in the literature , but has been identified in 1 individual with DCM tested by our laboratory. Com putational analyses (biochemical amino acid properties, conservation, AlignGVGD and PolyPhen2) do not provide strong support for or against an impact to the pro tein. Additional information is needed to fully assess the clinical significance of the Arg18358His variant. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 14, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 09, 2018 | The p.R11862H variant (also known as c.35585G>A), located in coding exon 131 of the TTN gene, results from a G to A substitution at nucleotide position 35585. The arginine at codon 11862 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported as NM_133378.4:c.55076G>A p.R18359H in an individual with dilated cardiomyopathy (DCM); however, clinical details were limited (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at